Immunometabolism and the Cardio-Renal Axis in T1D-associated Atherosclerosis: Insights from the CaRe T1D Biobank

Abstract
Cardiovascular disease (CVD) caused by atherosclerosis remains the leading cause of mortality in individuals
with type 1 diabetes (T1D). Although T cells are well known to play a critical role in T1D development,
attacking and destroying the insulin-producing β-cells, very little is known about the expansion of specific T cell
populations and clones in cardiovascular complications associated with T1D. Our project aims to dissect the
relationship between increased recruitment and expansion of harmful T cells in the atherosclerotic milieu of
T1D, leveraging the unique resources of the CaRe-T1D biobank. By employing single cell-T cell receptor-
sequencing (scTCR-seq) and cellular indexing of transcriptomes and epitopes-sequencing (CITE-seq) of
circulating PBMCs, we will illuminate T cell populations altered in T1D and investigate their adhesion to human
coronary artery endothelial cells. By performing TCR-seq on atherosclerotic lesions and elucidate localization
of T cell population associated with lesion stage by spatial and global proteomics we will delineate the role
these T cells might play in the increased CVD risk associated with T1D.
We hypothesize that atherosclerotic lesions in T1D are characterized by increased accumulation of specific
T cell populations and clones correlating with lesion severity and necrosis, and that the accumulation of T cells
in T1D-related atherosclerotic and renal kidney lesions mirror each other, driven by similar immunometabolic
perturbations. Two specific aims will address this hypothesis. We will 1) Clarify mechanisms of increased T cell
adhesion and tissue recruitment in T1D cases; and 2) Investigate clonal expansion of CD4+ and CD8+ T cells
in atherosclerotic lesions in T1D. By correlating selective T cell markers with a thorough characterization of
lesion features, our studies will provide novel information on T cells in the pathogenesis of atherosclerosis and
renal kidney injury in T1D in contrast with controls and T2D.
Our project is led by a coalition of scientists and physician-scientists with extensive expertise in diabetes,
diabetes complications (atherosclerosis and diabetic kidney disease) and immunology, with deep
methodological proficiency in human studies, multi-omics analyses, and integrated biology. This diverse
expertise ensures a holistic approach and full utilization of the unique resources of the CaRe-T1D, enabling us
to navigate the complex interplay of metabolic and immune processes in T1D with unparalleled depth and
precision. Our comparative analyses between peripheral blood mononuclear cells, atherosclerotic lesions and
kidneys from the CaRe-T1D biobank will provide a robust platform for identifying and testing potential
therapeutic targets. Our focus on the metabolic-immune interface within atherosclerotic lesions, and
specifically on identifying specific T cell populations and clones, offers a novel perspective on pathogenesis,
positioning our study to make significant contributions to the field.

Grant Number: 5U01DK142249-02
NIH Institute/Center: NIH
Principal Investigator: Karin Bornfeldt